Numerous compounds have been reported having therapeutically and/or prophylactically useful selective cyclooxygenase-2 inhibitory effect, and have been disclosed as having utility in treatment or prevention of specific cyclooxygenase-2 mediated disorders or of such disorders in general. Among such compounds are a large number of substituted pyrazolyl benzenesulfonamides as reported in U.S. Pat. No. 5,760,068 to Talley et al., including for example the compound 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, also referred to herein as celecoxib, and the compound 4-[5-(3-fluoro-4methoxyphenyl)-3-difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, also referred to herein as deracoxib. Celecoxib has the structure:
and deracoxib has the structure:

Other compounds reported to have therapeutically and/or prophylactically useful selective cyclooxygenase-2 inhibitory effect are substituted isoxazolyl benzenesulfonamides as reported in U.S. Pat. No. 5,633,272 to Talley et al., including for example the compound 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide, also referred to herein as valdecoxib, which has the structure:

Still other compounds reported to have therapeutically and/or prophylactically useful selective cyclooxygenase-2 inhibitory effect are substituted (methylsulfonyl)phenyl furanones as reported in U.S. Pat. No. 5,474,995 to Ducharme et al., including for example the compound 3-phenyl-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one, also referred to herein as rofecoxib, which has the structure:

U.S. Pat. No. 5,981,576 to Belley et al. discloses a further series of (methylsulfonyl)phenyl furanones said to be useful as cyclooxygenase-2-inhibitors, including 3-(1-cyclopropylmethoxy)-5,5dimethyl-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one and 3-(1-cyclopropylethoxy)-5,5-dimethyl-4-[4-(methylsulfonyl)phenyl]-5H-furan-2-one.
European Patent Application No. 0 863 134 discloses the compound 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one said to be useful as a cyclooxygenase-2 inhibitor.
International Publication No. WO 99/55380 discloses, inter alia, a compound having the structure:
said to be useful as a cyclooxygenase-2 inhibitor.
Many selective cyclooxygenase-2 inhibitory compounds, including celecoxib, deracoxib, valdecoxib and rofecoxib, are hydrophobic and have low solubility in water. This has presented practical difficulties in formulating such compounds for oral administration, particularly where early onset of therapeutic effect is desired or required.
Illustratively, the formulation of celecoxib for effective oral administration to a subject has hitherto been complicated by the unique physical and chemical properties of celecoxib, particularly its low solubility and factors associated with its crystal structure, including cohesiveness, low bulk density and low compressibility. Celecoxib is unusually insoluble in aqueous media. Unformulated celecoxib is not readily dissolved and dispersed for rapid absorption in the gastrointestinal tract when administered orally, for example in capsule form. In addition, unformulated celecoxib, which has a crystal morphology that tends to form long cohesive needles, typically fuses into a monolithic mass upon compression in a tableting die. Even when blended with other substances, the celecoxib crystals tend to separate from the other substances and agglomerate together during mixing of the composition resulting in a non-uniformly blended composition containing undesirably large aggregates of celecoxib. Therefore, it is difficult to prepare a pharmaceutical composition containing celecoxib that has the desired blend uniformity. Further, handling problems are encountered during the preparation of pharmaceutical compositions comprising celecoxib. For example, the low bulk density of celecoxib makes it difficult to process the small quantities required during formulation of the pharmaceutical compositions. Accordingly, a need exists for solutions to numerous problems associated with preparation of suitable pharmaceutical compositions and dosage forms comprising celecoxib, particularly orally deliverable dose units.
More generally, a need exists for orally deliverable formulations of cyclooxygenase-2 inhibitory drugs of low water solubility including celecoxib, such formulations possessing one or more of the following characteristics relative to unformulated celecoxib or other celecoxib compositions:                (1) improved solubility;        (2) shorter disintegration time;        (3) shorter dissolution time;        (4) decreased tablet friability;        (5) increased tablet hardness;        (6) improved wettability;        (7) improved compressibility;        (8) improved flow properties of liquid and particulate solid compositions;        (9) improved physical stability of the finished composition;        (10) reduced tablet or capsule size;        (11) improved blend uniformity;        (12) improved dose uniformity;        (13) improved control of weight variation during encapsulation and/or tableting;        (14) increased granule density for wet granulated compositions;        (15) Reduced water requirement for wet granulation;        (16) Reduced wet granulation time; and        (17) Reduced drying time for wet granulated mixtures.        
Further, there exists an especial need for orally deliverable formulations of cyclooxygenase-2 inhibitory drugs of low water solubility including celecoxib, such formulations providing more rapid onset of therapeutic effect than the corresponding unformulated drugs or known formulations of these drugs. To the extent that rapid onset of therapeutic effect is related to pharmacokinetic parameters such as a high maximum blood serum concentration of the drug (Cmax) and a short time from oral administration to reach such maximum blood serum concentration (Tmax), there is an especial need for orally deliverable formulations of cyclooxygenase-2 inhibitory drugs of low water solubility including celecoxib, such formulations providing a greater Cmax and/or an earlier Tmax than the corresponding unformulated drugs or known formulations of these drugs.
As is indicated herein below, treatment with selective cyclooxygenase-2 inhibitors including celecoxib is indicated or potentially indicated in a very wide array of cyclooxygenase-2 mediated conditions and disorders. It would be of benefit to provide formulations exhibiting pharmacokinetics consistent with rapid onset of therapeutic effect especially for treatment of acute disorders where early relief from pain or other symptoms is desired or required.
Such formulations would represent a significant advance in the treatment of cyclooxygenase-2 mediated conditions and disorders.
Cyclooxygenase-2 inhibitory drugs including celecoxib that are of low solubility in water are most conveniently formulated in solid particulate form. The individual or primary particles of the drug can dispersed in a liquid medium, as in a suspension formulation, or can be aggregated to form secondary particles or granules that can be encapsulated to provide a capsule dosage form, or compressed or molded to provide a tablet dosage form.
Numerous processes are known and used in the art for preparing drug formulations having primary particle sizes in a desired range, or having a desired mean particle size, or having a particle size distribution characterized by a parameter such as D90, which is defined herein as a linear measure of diameter having a value such that 90% by volume of particles in the formulation, in the longest dimension of the particles, are smaller than that diameter. For practical purposes a determination of D90 based on 90% by weight rather than by volume is generally suitable.
For consistency with prior publications, the terms “microparticle” and “nanoparticle” are defined herein as in U.S. Pat. No. 5,384,124 to Courteille et al., to refer to particles having respectively a diameter of between 1 micrometer and 2000 micrometers and a diameter of less than 1 micrometer (1000 nm). The preparation of microparticles and nanoparticles, according to U.S. Pat. No. 5,384,124, “is principally used to retard dissolution of active principles”. However, U.S. Pat. No. 5,145,684 to Liversidge et al. discloses nanoparticulate compositions said to provide “unexpectedly high bioavailability” of drugs, particularly drugs having low solubility in a liquid medium such as water. International Publication No. WO 93/25190 provides pharmacokinetic data from a rat study indicating a higher apparent rate of absorption from oral administration of a nanoparticulate (average particle size 240-300 nm) than from oral administration of a microparticulate (particle size range 20-30 micrometer) dispersion of naproxen.
Numerous processes for preparation of nanoparticulate compositions of therapeutic agents are known. Typically these processes use mechanical means, such as milling or grinding, to reduce particle size to a nano (less than 1 micrometer) range, or precipitate nano-sized particles from solution. Illustrative processes are disclosed in the following individual references: U.S. Pat. No. 4,826,689 to Violanto & Fischer, above-cited U.S. Pat. No. 5,145,684 to Liversidge et al., U.S. Pat. No. 5,298,262 to Na & Rajagopalan, U.S. Pat. No. 5,302,401 to Liversidge et al., U.S. Pat. No. 5,336,507 to Na & Rajagopalan, U.S. Pat. No. 5,340,564 to Illig & Sarpotdar, U.S. Pat. No. 5,346,702 to Na & Rajagopalan, U.S. Pat. No. 5,352,459 to Hollister et al., U.S. Pat. No. 5,354,560 to Lovrecich, above-cited U.S. Pat. No. 5,384,124 to Courteille et al., U.S. Pat. No. 5,429,824 to June, U.S. Pat. No. 5,510,118 to Bosch et al., U.S. Pat. No. 5,518,738 to Eickhoff et al., U.S. Pat. No. 5,503,723 to Ruddy & Eickhoff, U.S. Pat. No. 5,534,270 to De Castro, U.S. Pat. No. 5,536,508 to Canal et al., U.S. Pat. No. 5,552,160 to Liversidge et al., U.S. Pat. No. 5,560,931 to Eickhoff et al., U.S. Pat. No. 5,560,932 to Bagchi et al., U.S. Pat. No. 5,565,188 to Wong et al., U.S. Pat. No. 5,569,448 to Wong et al., U.S. Pat. No. 5,571,536 to Eickhoff et al., U.S. Pat. No. 5,573,783 to Desieno & Stetsko, U.S. Pat. No. 5,580,579 to Ruddy et al., U.S. Pat. No. 5,585,108 to Ruddy et al., U.S. Pat. No. 5,587,143 to Wong, U.S. Pat. No. 5,591,456 to Franson & Snyder, U.S. Pat. No. 5,662,883 to Bagchi et al., U.S. Pat. No. 5,665,331 to Bagchi et al., U.S. Pat. No. 5,718,919 to Ruddy & Roberts, U.S. Pat. No. 5,747,001 to Wiedmann et al., International Publication No. WO 93/25190, International Publication No. WO 96/24336, International Publication No. 98/35666.